👤 Vazhaikkurichi M Rajendran

The role of cell-specific ANGPTL4 is not well known in the context of ECs, specifically in pathological angiogenesis and its relation to diabetic kidney disease. Here, we demonstrate that endothelial ANGPTL4 is required to induce a metabolic phenotype that favors mesenchymal activation in ECs and tubules in diabetic conditions. Diabetes accelerates mesenchymal activation and fibrogenesis in control mice however, the same effects were not observed in endothelial-cell specific knock out mice. This mesenchymal activation in diabetes is directly linked with pathological neovascularization, endothelial leakage, lipid and glycolysis metabolite load, de novo lipogenesis (DNL) and related mitochondrial damage, activation of the immune system, c-GAS-STING activation and transcription of pro-inflammatory cytokines. However, endothelial ANGPTL4-depleted mice had stable vessels, improved levels of lipid and glucose metabolism, suppressed levels of DNL, restored mitochondrial function, and mitigated levels of c-GAS-STING-mediated inflammation. Moreover, Inhibition of DNL, and STING via small molecule inhibitors suppressed pathological neovascularization and endothelial leakage, normalized fatty acid oxidation and reduced pathological glycolysis and de novo lipogenesis (DNL). These data demonstrate the crucial roles of endothelial ANGPTL4 in regulating pathogenic angiogenesis in the renal vasculature during diabetes. Show less

FGF, VEGFR-2 and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg In the prevention experiment, treatment with 6.25 or 12.5 mg·kg Multi-kinase inhibition by fexagratinib in a well-tolerated dose of 1 mg·kg Show less

Background & objectives Central TB division facilitated development of a line probe assay (LPA) artificial intelligence (AI) tool. The tool was developed, trained, and validated for performance by collecting more than 18,000 LPA strips across culture and drug susceptibility Testing (C&DST) laboratories. The Indian Council of Medical Research (ICMR)-National Institute for Research in Tuberculosis (NIRT) evaluated the LPAAI tool independently. The objective was to establish and verify an AI-driven system for automatically interpreting LPA strips, which are employed in tuberculosis drug resistance screening, to improve accuracy, consistency, and scalability across diverse laboratory settings. Methods The AI system integrates faster regions convolutional neural network (FR-CNN) for strip detection, detection transformer (DETR) for band localisation, and a hierarchical neural network (HNN) for classification of bands, loci, and drug labels. Independent validation was conducted by ICMR-NIRT using 2810 first-line (FL)-LPA and 241 reflex second-line (SL-LPA) across ten intermediate reference laboratories (IRLs). Results AI comparative models demonstrated an accuracy range of 92-100 per cent, with sensitivity between 80-100 per cent and specificity from 86-100 per cent for the tub, rpoB, katG, InhA, gyrA/gyrB,rrs, and eisgenes. The overall F1 score varies from 0.81 to 1.00, indicating perfect precision and recall. Interpretation & conclusions This AI system offers a novel, modular architecture capable of expert-level interpretation of LPA strips. The AI tool performs at par with expert readers and offers a reliable, scalable solution for LPA interpretation.AI tool adoption can reduce interpretation time, enhance result uniformity, and improve treatment delivery across India's TB programme, supporting national goals for TB elimination. Show less

Angiopoietin-like 4 (ANGPTL4), a key protein involved in lipoprotein metabolism, has diverse effects. There is an association between Angptl4 and diabetic kidney disease; however, this association has not been well investigated. We show that both podocyte- and tubule-specific ANGPTL4 are crucial fibrogenic molecules in diabetes. Diabetes accelerates the fibrogenic phenotype in control mice but not in ANGPTL4 mutant mice. The protective effect observed in ANGPTL4 mutant mice is correlated with a reduction in stimulator of interferon genes pathway activation, expression of pro-inflammatory cytokines, reduced epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition, lessened mitochondrial damage, and increased fatty acid oxidation. Mechanistically, we demonstrate that podocyte- or tubule-secreted Show less

Sterubin (7-O-Methyleriodicytol), a flavanone compound isolated from the leaves of Eriodicyton californicum and Eriodicyton angustifolium, has neuroprotective, anti-inflammatory, and antioxidant properties. Therefore, it is of interest to identify the potential targets for Alzheimer disease using network pharmacology. We report 25 overlapping targets among 100 potential targets of sterubin and 673 known targets of Alzheimer. APP, BACE-1, and AChE were among the ten hub targets enriched in biological processes and pathways relevant to Alzheimer's disease. Subsequent, molecular docking analysis shows that sterubin have optimal binding features with these hub gene targets for further consideration. Show less

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG) Show less

Glucose-dependent insulinotropic polypeptide (GIP) secreted from jejunal mucosal K cells augments insulin secretion and plays a critical role in the pathogenesis of obesity and Type 2 diabetes mellitus. In recent studies, we have shown GIP directly activates Na-glucose cotransporter-1 (SGLT1) and enhances glucose absorption in mouse jejunum. It is not known whether GIP would also regulate other intestinal nutrient absorptive processes. The present study investigated the effect of GIP on proton-peptide cotransporter-1 (PepT1) that mediates di- and tripeptide absorption as well as peptidomimetic drugs. Immunohistochemistry studies localized both GIP receptor (GIPR) and PepT1 proteins on the basolateral and apical membranes of normal mouse jejunum, respectively. Anti-GIPR antibody detected 50-, 55-, 65-, and 70-kDa proteins, whereas anti-PepT1 detected a 70-kDa proteins in mucosal homogenates of mouse jejunum. RT-PCR analyses established the expression of GIPR- and PepT1-specific mRNA in mucosal cells of mouse jejunum. Absorption of Gly-Sar (a nondigestible dipeptide) measured under voltage-clamp conditions revealed that the imposed mucosal H(+) gradient-enhanced Gly-Sar absorption as an evidence for the presence of PepT1-mediated H(+):Gly-Sar cotransport on the apical membranes of mouse jejunum. H(+):Gly-Sar absorption was completely inhibited by cephalexin (a competitive inhibitor of PepT1) and was activated by GIP. The GIP-activated Gly-Sar absorption was completely inhibited by RP-cAMP (a cAMP antagonist). In contrast to GIP, the ileal L cell secreting glucagon-like peptide-1 (GLP-1) did not affect the H(+):Gly-Sar absorption in mouse jejunum. We conclude from these observations that GIP, but not GLP-1, directly activates PepT1 activity by a cAMP-dependent signaling pathway in jejunum. Show less